All motor commands must be processed by motoneurons before muscle force can be generated. The dendrites of motoneurons are highly active, in large part due to voltage-sensitive currents that tend to be long lasting. These persistent inward currents (PICs) can amplify synaptic input as much as 5-10 fold, but this amplification is proportional to the level of neuromodulatory input from brainstem nuclei whose axons release the monoamines serotonin and norepinephrine. Progressively, work in our lab has moved from studying cellular properties of dendritic PICs to understanding their functional implications for motor control, most especially during posture. This approach has lead to the realization that spinal interneurons, especially the Ia interneurons that mediate reciprocal inhibition between antagonist muscle groups, are fundamentally important for PIC control. The need for inhibitory control arises from the fact that, for all their advantages, dendritic PICs also induce potentially severe deficits in synaptic processing. These deficits include slow, inconsistent activation and a strong tendency to prolong inputs for many seconds, thus severely distorting dynamic inputs. Our basic hypothesis is that good control of PICs in motoneurons requires Ia reciprocal inhibition to be linked with motor commands to motoneurons in a push-pull fashion. In this concept, push-pull control of PICs works from a tonic background of both excitatory and inhibitory input, so that depolarization is generated equally by excitation and by disinhibition (and vice versa for hyperpolarization). To evaluate this hypothesis, we have 4 aims: 1) to investigate whether push-pull control relying on Ia reciprocal inhibition can provide PIC amplification without PIC deficits; 2) to compare push-pull to other control schemes for using inhibition to control the PIC; 3) to measure the input-output properties of the Ia reciprocal inhibitory system, to determine if this system provides appropriate proportional relations for good push-pull; and 4) to determine whether the steady background of Ia inhibition required for push-pull control of PICs induces high conductance or high noise states in motoneurons, as it appears occur for push-pull in cortical cells. Overall, push-pull control would allow descending systems to adjust motoneuron gain via monoaminergic effects on PICs while maintaining good dynamic behavior. Push-pull would also account for the tendency of spinal interneurons to be tonically active even when no movements are generated and for electrical stimulation of descending systems to evoke a mixture of excitation and inhibition in motoneurons. Moreover, these studies are likely highly relevant to understanding motoneuron hyper-excitability in stroke, where loss of volitional control of Ia reciprocal inhibition may prevent normal push-pull control and allow uncontrolled PIC behavior. PUBLIC HEALTH RELEVANCE: All motor commands are processed by motoneurons before generating muscle force. The proposed research evaluates a new concept of the organization of motor commands to the spinal cord, i.e. that motoneurons require inputs with a push-pull structure based on inhibitory spinal interneurons that link antagonist muscle groups in posture and other motor behaviors. This new concept of motor commands is important for understanding hyper-excitability in hemiparetic stroke patients, where voluntary control of the necessary inhibitory interneurons is missing.